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11Thiazole: A privileged scaffold in drug discovery 249
O
N
2
S
+
H2NNH
2
Cu(OTf)
DCE, 80°C
2
S
NH
N
2
2726
Scheme 11.4: Synthesis of 2-amino-4-phenyl thiazoles from α–diazoketones.
Castagnolo and co-workers reported a microwave mediated domino alkylation-cyclization reaction of propargyl bromides (28) with thioureas to synthesize 2-aminothiazoles (29) in high yields (Scheme 11.5) [20].
S
+
Br
1
NR
H
2
R
2
N
H
(1 eq.)
K
2CO3
DMF , MW,
130°C, 2.5 min.
28 29
Scheme 11.5: Synthesis of 2-amino-4-benzyl thiazoles from propargyl bromides.
R
N
1
NHR
S
= C6H
R
2
1
5
R2 = C6H5,p–CL–C6H4,
p–CH
3–C6H4
etc.
A series of disubstituted thiazoles 31 were synthesized by Miyamoto et al. via the
cyclocondensation of 1-alkynyl(phenyl)-λ
3
-iodanes (30) with thioureas or thioamides
in the presence of a base, such as potassium carbonate or triethylamine (Scheme 11.6)
[21].
R
I
R
1
Ph
X
S
+
R
2
NH
2
K2CO3 or Et3N
1
N
S
R
2
R1 = C6H
R2 = CH
n–Bu
5,
3, C6H5
X = OMs
3130
Scheme 11.6: Synthesis of 2,4-disubstituted thiazoles using hypervalent iodine reagents.
Several 2,4-disubstituted-5-acetoxythiazoles (35) were synthesized by reacting methyl
thiobenzoate derivatives (33), obtained from methyl benzoate 32, with racemic
phenylglycine (34) in a two-phase solvent system composed of 3N NaOH and ether.
The coupled product on subsequent treatment with acetic anhydride resulted in
desired thiazole derivatives 35 (Scheme 11.7) [22].
250 Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke*
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S
Ar
O
O
Ar
32
Ar = C
3–Cl–C
MW. 150°C, 1h
O
, 4–CH3C6H4,
6H5
, 2–thienyl etc.
6H4
P
4S10
, HMDO
33
+
Ph
N
H
2
(i) NaOH-ether,
rt
(ii) Ac
O
OH
O
2
34
Ph
AcO
N
Ar
S
35
Scheme 11.7: Synthesis of trisubstituted thiazoles from phenylglycine.
A trisubstituted diverse library of thiazoles (37, Scheme 11.8) was synthesized by
Cervera et al. which involves the double acylation of a protected glycine to α-amidoβ-ketoesters (36). The intermediate 36 on reaction with Lawesson’s reagent resulted
in the formation of the desired benzyl 2,5-substitutedthiazole-4-carboxylate scaffold
(37) [23].
O
R
O
R
1
2
N
COOBn
H
L.R. (2 eq.)
THF, reflux, 14h
36
BnOOC
N
S
R
2
R1 = NH2, CH3, C6H
R
1
R2 = CH3, C6H5, p–CH3–C6H4 etc.
5
37
Scheme 11.8: Synthesis of trisubstituted thiazoles using Lawesson’s reagent.
Several reports on the two stage synthesis of thiazoles involving cyclization of cysteine
side-chains onto carbonyl groups followed by oxidative aromatization are reported in
the literature. Following this approach, L-cysteine ethyl ester (38) was reacted with
variously substituted aldehydes to afford the corresponding thiazolidine derivatives
39, which on further oxidation with MnO
resulted in disubsituted thiazoles 40 as
2
shown in Scheme 11.9 [24].
SH
+
RCHO
EtOOC
NH
2
38
R = 2–pyridyl, 4–COOC
H2O, CH3OH
2H5–C6H4
KHCO
etc.
3
EtOOC
S
N
H
MnO2 (5 eq.)
R
Toluene
39 40
Scheme 11.9: Synthesis of 4-carbethoxy thiazoles from L-cysteine methyl ester.
R
COOEt
N
S
11Thiazole: A privileged scaffold in drug discovery 251
An efficient synthesis of ethyl 2-dimethylaminothiazole-4-carboxylates (44) was
described by Yavari et al. via a four component reaction between acid chlorides (41),
α-bromoethyl pyruvate (42), secondary amines (43) and ammonium thiocyanate
(Scheme 11.10) [25].
R
1
N
R
2
N
S
R
3
NH4SCN
O
++ +
R
1
Br
Cl
COOEt
O
R
3
Acetone
N
rt, 1h
H
R
2
41 42 43 44
EtOOC
O
R1 = C6H5, 4-CH3-C6H4, 4-Br-C6H4, 4-NO2-C6H4, C2H
R2, R3 = CH3, (CH2)4, (CH2)5, (CH2)2O(CH2)
2
5
Scheme 11.10: Multicomponent synthesis of trisubstituted thiazoles.
Three differently substituted thiazoles (47–49) have been synthesized from commer-
cially available propargylic alcohols (45) and amides (46) using Lawesson’s reagent
[26]. A diverse set of compounds were synthesized by these authors using a wide
range of secondary propargylic alcohols and/or tertiary propargylic alcohols bearing
both terminal as well as internal alkyne groups. Several trisubstituted thiazoles with
functional groups, such as cyclopropyl, cyclohexenyl, halogens, esters and methoxy
groups are synthesized under these reaction conditions (Scheme 11.11).
HO
Ph
R
45
(i) FeCl3 (10 mol%),
CH3CN
(ii) L.R., toluene
Ph
N
S
1
O
++
R
1
R
NH
2
2
R
CSNH
2
2
10 mol%, AgOTf
C6H5Cl, reflux
Ph
N
R
2
S
R
1
48 4946
R1 = C6H5, TMS
R2 = C6H5, 4–CH3–C6H4, 4–Cl–C6H4 etc.
R
2
N
R
1
Ph
R
2
S
47
Scheme 11.11: Synthesis of trisubstituted thiazoles from propargylic alcohols.
252 Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke*
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11.3 Thiazole as privileged scaffold in synthetic drugs
A wide range of pharmacological activities in thiazole-containing natural and synthetic products including several drugs in clinical use (Table 11.1) illustrate well the
importance of this heterocycle in today’s life. Elaboration of a few of these molecules
in terms of their structure, synthetic route and mechanism of biological action are
discussed further.
11.4 Ritonavir
Ritonavir (50) is the first and the only thiazole-containing antiretroviral drug from the
protease inhibitor class used to treat HIV infection and AIDS. Structurally, it is a carboxamide of L-valine and 2,5-diamino-1,6-diphenylhexan-3-ol linked to two thiazole
rings. At one end, 5-thiazolylmethanol is coupled via a carbamate linker while other
end forms a urea linkage with 1-(2-isopropylthiazol-4-yl)-N-methylmethanamine.
50
Ph
Ph
OH
O
N
O
H
N
S
O
N
S
Fig. 11.5: Chemical structure of ritonavir.
N
N
H
H
N
O
Ritonavir, originally developed as HIV protease inhibitor, is frequently prescribed
with a highly active antiretroviral therapy (HAART). It potently induces CYP 1A2
and inactivates cytochrome P450 3A4 (CYP 3A4), a major human drug-metabolizing
enzyme. The CYP3A4 inhibition increases the plasma concentrations of other antiHIV drugs improving the overall clinical efficacy of HAART [27].
The effect of ritonavir on the redox properties of the hemoprotein was investigated by Sevrioukova et al. [28]. The study of the CYP 3A4-ritonavir binding reaction
by kinetic and equilibrium analysis and the 2.0 Å X-ray structure of this complex confirmed ritonavir as a type II ligand that perfectly fits into the CYP 3A4 active site cavity.
This investigation also confirmed the irreversible binding of ritonavir to the heme iron
via thiazole nitrogen, decreasing the redox potential of the protein and preventing its
reduction with the redox partner, cytochrome P450 reductase. Based on their observations, the thiazole nitrogen of ritonavir is the likely iron ligand in both ferric and
ferrous CYP 3A4 and therefore concluded that the thiazole and isopropyl thiazole
groups of ritonavir are strictly required for the observed inhibitory activity [29].
11Thiazole: A privileged scaffold in drug discovery 253
Treatment of HIV infection
andAIDS. Frequently prescribed
with ahighly active antiretroviral
HIV protease inhibitor class,
therapy(HAART).
induces CYP A and inactivates
Cytochrome P A enzyme and
increases plasma concentration of
N
S
other anti-HIV drugs.
Treatment of illness caused byCryp-
Prevent the production of acetyl
tosporidium parvumorGiardia
lambliaand other protozoa and
CoA within anaerobic bacteria and
parasites by inhibiting pyruvate/
helminthes infections. Also used for
ferredoxin reductase. Effective
the treatment of chronic hepatitis
inhibitors of HBV and in some cases
B and C infection as well as small
intestinal bacterial overgrowth.
of hepatitis C virus (HCV) replication
in cell cultures.
Sulfonamides are broad-spectrum,
Sulfonamides are competitive
bacteriostatic anti-infectives.
inhibitors of a bacterial enzyme,
dihydropteroate synthetase. This
inhibition blocks the synthesis of
dihydrofolic acid and decreases
Thiabendazole is used primarily as
fungicide in fruits and vegetables
and as an antiparasitic agent to
controlroundwormswhich attack
animals and humans.
the amount of metabolically active
tetrahydrofolic acid.
Thiabendazole inhibits the
mitochondrial helminth-specific
enzyme, fumarate reductase with
anthelminthic property.
Table 11.1: Structure, pharmacological activity and clinical use of thiazole-containing drugs.
No. Name Structure Pharmacological activity Clinical use
O
O
N
H
Ph
H
O
Ritonavir
OH
Ph
N
O
N
H
N
N
S
2
NO
Nitazoxanide
N
S
N
H
OO
O
S
O
O
Sulfathiazole
N
S
N
H
N
S
N
H
N
N
2
H
Thiabendazole
254 Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke*
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Potential drug candidate to block
adipogenesis. It can help combat
obesity and may help diabetes. It
also displays high antitumor activ-
(SREBP).
ity in prostate cancer.
Used for the treatment of chronic
Bcr-Abl and Src family tyrosine
Antifungal agent.
Ravuconazole is a triazoleantifun-
gal agent from the class ergosterol
biosynthesis inhibitor. Inhibits
Cytochrome P- dependent C-
Thiamethoxamis a systemicinsecti-
cidein the class ofneonicotinoids.
It has a broad spectrum of activity
against many types of insects.
Inhibits activation of sterol
Known to paralyze the muscles of
insects by affecting the transfer of
information between nerve cells via
interfering withnicotinic acetylcho-
line receptorsin thecentral nervous
demethylation of lanosterol, a key
step in ergosterol biosynthesis.
system.
regulatory element-binding protein
myelogenous leukemia (CML),
Philadelphia chromosome-positive
acute lymphoblastic leukemia (Ph +
ALL) and advanced prostate cancer.
kinase inhibitor.
No. Name Structure Pharmacological activity Clinical use
N
N
Ravuconazole
OH
N
3
CH
N
N
N
N
S
F
OH
F
N
Cl
N
S
N
O
N
N
O
NC
Thiamethoxam
N
N
C
O
3
H
Fatostatin
C
3
N
H
S
N
H
N
S
O
H
N
3
Cl
CH
Dasatinib
11Thiazole: A privileged scaffold in drug discovery 255
It possesses significant activity
against both human lymphoid,
lung tumor cell lines and murine-
implanted human ovarian cancers.
Useful in the treatment of hemato-
logical and solid tumors.
It is an inosine-'-monophosphate
(IMP) dehydrogenase inhibitor.
Inhibitor of Aurora kinases A and B
and VEGFR.
Microtubule depolymerizing
Inhibits VEGF-induced phosphoryla-
activity.
tion of VE-cadherin (VE-cadherin
is crucial for controlling the state
of adherence junctions, which in
turn regulate endothelial cell–cell
adhesion, cell motility, morpho-
genesis and intracellular signaling
pathways).
Useful in the treatment of cancer
Histone deacetylase (HDAC)
and antiproliferative agent.
inhibitor.
No. Name Structure Pharmacological activity Clinical use
Table 11.1: (continued)
2
NH
N
S
O
HO
Tiazofurin
2
SH
NH
N
S
O
OH
HO
CYC
N
N
H
N
O
O
O
O
H
N
S
O
S
N
O
N
N
2
H
TR-
N
NCH-
256 Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke*
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Inhibitor of tubulin polymerization. Used against murine and human
N
COX- inhibitor. NSAID with analgesic and fever
reducer effects.
activity.
COX- inhibitor. NSAID and immunoregulating
inflammatory diseases such as
rheumatoid arthritis (RA) and
solid tumors.
inflammatory bowel disease (IBD).
p MAP kinase inhibitor. Used in the treatment of chronic
O
OO
O
N
N
N
S
N
H
O
2
NH
H
Ph
O
N
N
N
S
S
N
N
H
N
O
OH O
S
N
S
N
H
O
No. Name Structure Pharmacological activity Clinical use
CKD-
TAK-
Meloxicam
Fanetizole
11Thiazole: A privileged scaffold in drug discovery 257
and has analgesic and antipyretic
activity
Reduces systolic blood pressure.
Used to treat duodenal ulcers,
-receptor antago-
gastric ulcers and gastroesophageal
refluxdisease.
Nizatidine is a more effective HRA
than famotidine in the maintenance
therapy of patients with reflux
esophagitis.
COX- inhibitor. NSAID for joint and muscular pain
COOH
–pCl
4
H
6
C
S
N
Ph
Disruption of crosslinks caused by
advanced glycation end products
S
N
O
(AGEs).
HistamineH
nist (HRA) that inhibitsstomach
acidproduction.
O
S
O
N
2
NH
S
Cl
N
2
NH
N
N
2
H
NH
In addition to the acid-suppressing
effect, the HRA nizatidine also has
a prokinetic action by suppressing
acetylcholine esterase.
2
2
NO
NH
H
N
S
S
N
S
N
No. Name Structure Pharmacological activity Clinical use
Table 11.1: (continued)
Fentiazac
Alagebrium
Famotidine
Nizatidine
258 Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke*
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Ritonavir has an elongated shape (Fig.11.5), which can enter the CYP 3A4 active
site with either the thiazole or isopropyl-thiazole end. Based on the observations of
Koudriakova and co-workers, CYP 3A4 mediates the hydroxylation of the latter group
and is unlikely to serve as a heme ligand suggesting a positional/conformational rearrangement when ritonavir docks to CYP 3A4 with the isopropylthiazole head to bring
the opposite thiazole moiety in the vicinity of the heme iron. The authors also suggested a possibility of dissociation and re-entry of the drug in the active site pocket to
achieve the appropriate orientation [30].
During the synthesis of ritonavir (Scheme 11.12), the urea linked disubstituted
thiazole ring was introduced by the reaction of dipeptide (51) with (4-isopropylthiazol-2-yl)-N-methylmethanamine (52), using triphosgene [bis(tri-chloromethyl)carbonate (BTC)] and Et
N in DCM to furnish 3-((S)-1-((2S,4S,5S)-5-(dibenzylamino)-4-hy-
3
droxy-1,6-diphenylhexan-2-ylcarbamoyl)-2-methylpropyl)-1-((2-isopropylthiazol-4-yl)
methyl)-1-methylurea (53). Hydrogenation of 53 in the presence of Pearlman’s catalyst [Pd(OH)
/C] afforded intermediate 54, this on further heating with 4-nitrophenyl
2
(thiazol-5-yl)methyl carbonate (55) in ethyl acetate for 12 hours resulted in Ritonavir
50 [31].
Ph
CH
Ph
2
N
OH
CH
Ph
Ph
51
N
2
O
OO
55
EtOAc,
60°C, 12 h
S
H2N
Ritonavir
50
H
N
O
O
2
Scheme 11.12: Synthesis of ritonavir.
H
N
BTC
Et
N
S
52
N, DCM
3
Ph
Ph
Ph
OH
OH
Ph
CH
Ph
2
N
CH
Ph
2
2
NH
2
N
S
S
O
N
N
O
N
N
H
N
N
H
O
53
H
, Pd(OH)
2
AcOH
H
N
N
H
O
54
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